Abstract PR011: Targeting cellular plasticity-driven metabolic adaptation to overcome chemoresistance in GBM
Authors: Atique U. Ahmed, Jack M. Shireman, Fatemeh Atash, Gina Lee, Eunus S. Ali, Miranda R. Saathoff, Cheol H. Park, Sol Savchuk, Shivani Baisiwala, Jason Miska, Maciej S. Lesniak, C. David James, Roger Stupp, Priya Kumthekar, Craig M. Horbinski, Issam Ben-Sahra
Journal: Cancer Research (2022)

Abstract Glioblastoma is an incredibly aggressive primary brain tumor that is universally lethal due to 100% recurrence. Recent research has pointed to the existence of a population of cells that possess stem cell-like characteristics that are resistant to conventional therapy and can initiate recurrence. Our laboratory, along with others, has demonstrated that this stem-like state is plastic and can be acquired by otherwise differentiated GBM cells exposed to different stress, including stress generated by chemotherapy. Our Initial investigation indicated that Polycomb group protein EZH2 is critical for therapeutic stress-induced cellular plasticity. Further investigation revealed that the mechanisms of EZH2-mediated cellular plasticity are partly governed by a novel downstream target ARL13B, a member of the ADP-ribosylation factor-like family protein critical for cilia formation and maintenance. ARl13B removal significantly reduced different stemness factors such as nestin, SOX2, and most importantly, sensitized different subtypes of patient-derived xenograft lines to temozolomide-based chemotherapy both in vitro and in vivo (p&amp;lt;.0001). Mass spectroscopy analysis revealed that ARL13B could directly interact with inosine monophosphate dehydrogenase 2 (IMPDH2), the rate-limiting enzyme purine biosynthesis. We further show that interaction between ARL13B and IMPDH2 is necessary for utilization of the de novo pathway during chemotherapy temozolomide (TMZ) treatment in that loss of ARL13B enhanced salvage (p-value&amp;lt;0.0001) and reduced de novo activity (p-value&amp;lt;0.0001). Loss of ARL13B causes a significant increase in DNA double-strand breaks in a TMZ-dependent manner as measured by γH2AX foci staining (p-value&amp;lt;0.0001). Based on these data, we propose that blocking the switch from salvage to de novo synthesis will force the tumor cells to recycle the damaged purines, thus effectively sensitizing them to TMZ therapy. By using an FDA-approved inhibitor of IMPDH2, mycophenolate mofetil (MMF), we have demonstrated that concurrent treatment with TMZ and MMF confers a significant survival benefit in the patient-derived orthotopic xenograft mouse models (p-value=0.004). Therefore, we proposed that the cellular plasticity driven ARL13B-IMPDH2 regulated switch from the salvage pathway to the de novo purine biosynthesis pathway is necessary for GBM cells’ adaptation to alkylating-based chemotherapy, and we are now starting a clinical trial to test this hypothesis. Citation Format: Atique U. Ahmed, Jack M. Shireman, Fatemeh Atash, Gina Lee, Eunus S. Ali, Miranda R. Saathoff, Cheol H. Park, Sol Savchuk, Shivani Baisiwala, Jason Miska, Maciej S. Lesniak, C. David James, Roger Stupp, Priya Kumthekar, Craig M. Horbinski, Issam Ben-Sahra. Targeting cellular plasticity-driven metabolic adaptation to overcome chemoresistance in GBM [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR011.